The present invention relates to an antipsychotic composition and to a method of treatment of patients suffering from serious psychotic mental illness.
Conventional antipsychotic drugs, termed "typical antipsychotics," are effective in improving symptoms of schizophrenia by acting as dopamine receptor antagonists, more particularly D.sub.2 dopamine receptor antagonists, which also are known as D.sub.2 dopamine receptor blockading agents. Such activity decreases the activity of the brain neurotransmitter dopamine. See Snyder, Am. J. Psychiatry 133: 197-202 (1976); Creese et al., Science 192: 481-83 (1976); Seeman et al., Nature 251: 717-19 (1976). Typical antipsychotics include those drugs known as "typical neuroleptics," exemplary of which are chlorpromazine, fluphenazine, trifluoperazine and haloperidol, among others. But a significant number of patients suffering from schizophrenia have proven resistant to treatment with typical neuroleptics.
It was previously found that clozapine, an "atypical neuroleptic"--that is, an antipsychotic neuroleptic which produces few or no extrapyramidal side effects ["EPSs"] and does not cause catalepsy in animal models)--is effective in treating patients suffering from schizophrenia who had shown poor response to other drugs. Kane et al., Arch. Gen. Psychiatry 45:789-96 (1988). The mechanism of action of clozapine includes .alpha..sub.2 -adrenergic receptor antagonism, in addition to a dopamine-blockading action which is characteristic of typical antipsychotic neuroleptics. See Pickar et al., Arch. Gen. Psychiatry 49: 345-53 (1992) (cited hereafter as "Pickar et al.").
Use of clozapine is associated with severe side effects, however, including agranulocytosis, seizures and adverse cardiovascular effects. See, for example, THE PHYSICIANS' DESK REFERENCE (1992), pages 1942-45; Griffith et al., Lancet 2: 657 (1979).